Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
  • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
  • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
  • C07D243/24—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• Cyclic nucleotide phosphodiesterase inhibitors preparation and uses of these inhibitors
• the invention relates to new benzodiazepinone derivatives and their applications in the therapeutic field, particularly for the treatment of pathologies involving the activity of a cyclic nucleotide phosphodiesterase. It also relates to processes for their preparation and to new synthesis intermediates.
• the compounds whose synthesis is described in the present invention are new and have very advantageous pharmacological properties: they are inhibitors of phosphodiesterases of cyclic nucleotides and very particularly of cAMP-phosphodiesterase type 4 (PDE4), and as such , they present very interesting therapeutic applications.
• PDE4 cAMP-phosphodiesterase type 4
• the functions of most tissues are modulated by endogenous (hormones, transmitters, etc.) or exogenous substances. Some of these substances have their biological effect relayed at the intracellular level by enzymatic effectors, such as adenylate cyclase or guanylate cyclase.
• cyclic AMP cyclic AMP
• cGMP cyclic GMP
• PDE phosphodiesterases
• PDE4 inhibitors by slowing the degradation of cyclic AMP, increase or maintain the level of cAMP in cells, and find their application in particular in the treatment of inflammatory diseases or pathologies of the tracheobronchial smooth muscles, by associating both an anti-inflammatory effect to a relaxation of smooth muscle.
• the Applicant has now demonstrated the inhibitory effects of cyclic nucleotide phosphodiesterases of certain benzodiazepines or benzodiazepinones, in particular PDE4 inhibitors.
• the invention also describes new compounds exhibiting a potent PDE4 inhibitory activity, and preferably having an excellent selectivity profile with respect to other PDE isoforms, in particular a weak action on PDE3.
• the preferred compounds according to the invention have anti-inflammatory properties which can be used as such to treat disorders of the central or peripheral nervous system, and are advantageously devoid of hypotensive or emetic effects.
• a more particular subject of the invention is compounds of general formula (I)
• X represents a group NR and Y represents a group CR 6 R 6 ', Rj, R 6 and R 6 ' being as defined below,
• Z represents an oxygen or sulfur atom.
• Ri is a (C ⁇ -Cn) alkyl, (C 3 -C 6 ) cycloalkyl, (C 6 -C 18 ) aryl, (C 6 -C 18 ) aryl (Cr C) alkyl, (C 1 -C 12 ) group (C 6 -C 18 ) alkyl aryl, a (C 5 -C 18 ) heterocycle, aromatic or not, comprising 1 to 3 heteroatoms, or an OR 2 , SR 2 or NR 2 R 3 group in which (i) R 2 and R 3 , independently of one another, are chosen from a hydrogen atom, a (CrC 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 6 -C 12 ) aryl group, or a heterocycle in (C 5 - C 12 ), aromatic or not, comprising 1 to 3 heteroatoms or, (ii) R 2 and R 3 together form a linear or branched hydrocarbon chain
• R 4 and t ' represent a (C 3 -C 6 ) cycloalkyl group, (C 6 -C 18 ) unsubstituted aryl, (C 6 -C 18 ) aryl (CrC 4 ) alkyl, (C 1 -C 12 ) (C 6 -C 18 ) alkyl aryl or a (C 5 -C 18 ) heterocycle, aromatic or not, comprising 1 to 3 heteroatoms, and, when X is the group CR 4 R ', ⁇ and R 4 ', identical or different, are also chosen from the hydrogen atom and a (C ⁇ -Cn) alkyl, (C 6 -C 18 ) aryl, (C 2 -C 6 ) alkenyl, (C 2 - C 6 ) alkynyl, NO 2 , CF 3 , CN, NR'R ", SR ', OR', COOR ', CONR'R"
• R 6 and R ⁇ ' are chosen from the hydrogen atom, a (Ci-Ce) alkyl, (C 6 -C 18 ) aryl, (C 6 -C 18 ) aryl (C 1 -C 4 ) alkyl, (C 1 -C 12 ) (C 6 -C 18 ) alkyl aryl, preferably a phenyl, benzyl group and a (CC 6 ) alkylphenyl group;
• R and R 8 independently of one another, are chosen from the hydrogen atom, a (Ci-C 1 ) alkyl group and an OR 2 group, R 2 being as defined above, with the condition that R 7 and R 8 do not simultaneously represent a hydrogen atom, or R 7 and R 8 together form a linear or branched hydrocarbon chain having 2 to 6 carbon atoms, optionally comprising one or more double bonds and / or possibly interrupted by an oxygen, sulfur or nitrogen atom
• the invention also relates to pharmaceutical compositions comprising one or more compounds of general formula (I) as defined above,
• the invention also relates to the use of the compounds of general formula (I) as defined above for the preparation of a pharmaceutical composition intended for the inhibition of a phosphodiesterase of cyclic nucleotides, in particular of phosphodiesterase 4 (PDE4 ).
• PDE4 phosphodiesterase 4
• the invention relates more particularly to the use of the above compounds for the treatment of pathologies involving deregulation of intracellular levels of cyclic AMP.
• alkyl denotes a linear or branched hydrocarbon radical advantageously having from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, n -hexyl, n-decyl, n-dodecyl, etc. C ⁇ -C groups are preferred.
• the alkyl groups may be substituted by an aryl group as defined below, in which case we speak of an arylalkyl group. Examples of arylalkyl groups include benzyl and phenetyl.
• cycloalkyl designates a cyclic hydrocarbon system, which can advantageously comprise from 3-6 carbon atoms and be mono- or polycyclic. Mention may in particular be made of cyclopropyl and cyclohexyl groups.
• the “aryl” groups are mono-, bi- or tri-cyclic aromatic hydrocarbon systems, preferably monocyclic or bi-cyclic aromatic hydrocarbon systems having from 6 to 18 carbon atoms, also more preferably 6 carbon atoms. Mention may be made, for example, of the phenyl, naphthyl and bi-phenyl groups.
• heterocycles denote aromatic or non-aromatic hydrocarbon systems comprising one or more cyclic heteroatoms. They are preferably cyclic hydrocarbon systems comprising from 5 to 18 carbon atoms and 1 or more cyclic heteroatoms, in particular from 1 to 3 or to 4 cyclic heteroatoms chosen from N, O or S.
• aromatic heterocyclic groups (heteroaryl) preferred, there may be mentioned in particular the thienyl, benzothienyl, benzofuryl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, isoquinoline, isoquinolinyl, morpholino, thiazolyl, furyl, pyranyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, benzymidazolyl, and pyrazolyl.
• the preferred non-aromatic heterocyclic groups there may be mentioned in particular the piperidinyl and pyrrolidinyl groups.
• the aryl and heterocycles groups can be substituted by an O ⁇ radical, an alkyl, alkenyl or alkynyl group.
• an aryl or a heterocycle substituted by an alkyl group we speak of an alkylaryl or alkylheterocycle group. of the examples of alkylaryl groups include toryl, mesythyl and xylyl.
• alkenylaryl groups we speak of an alkenylaryl or alkenyl heterocycle group.
• alkenylaryl groups are in particular the cinnamyl group.
• an aryl or a heterocycle substituted by an alkynyl group we speak of an alkynylaryl or alkynylheterocycle group.
• the aryl and heterocycles groups can also be substituted by a group chosen independently from the aryl or heterocycle groups, themselves optionally substituted by one or more substituents preferably chosen from a halogen atom or an NO 2 , CN, CF 3 group , OR ', COR', COOR ', alkoxy, NHCOR' and CONR'R '', R 'and R "being as defined above.
• aryl and heterocycles groups substituted by an aryl or heterocycle group are in particular the benzothienyl, benzofuryl, furylphenyl, benzyloxynaphthyl, pyridylphenyl, phenylphenyl and thienylphenyl groups.
• the above groups can be substituted. Mention may be made in this connection of phenyl groups substituted by a phenyl group itself substituted by a halogen atom, a NO, CF 3 , methoxy or methyl group.
• alkenyl groups are linear or branched hydrocarbon radicals comprising one or more double bonds, such as for example the allyl group. They advantageously contain from 2 to 6 carbon atoms and, preferably, 1 or 2 double bonds.
• the alkenyl groups can be substituted by an aryl group as defined above, in which case we speak of an arylalkenyl group.
• alkynyl groups are linear or branched hydrocarbon radicals comprising one or more triple bonds, such as for example the group 3- (benzyloxy) prop-1-ynyl, phenylethynyl, prop-2-ynyl and tert-butyl-prop- 2- ynylcarbamate. They advantageously contain from 2 to 6 carbon atoms and, preferably, 1 or 2 double bonds.
• the alkynyl groups can be substituted by an aryl group as defined above, in which case we speak of an arylalkynyl group.
• alkoxy groups correspond to the alkyl and cycloalkyl groups defined above linked to the nucleus via an —O— (ether) bond. Particularly preferred are methoxy or ethoxy groups.
• halogen is meant a fluorine, chlorine, bromine or iodine atom.
• heteroatom is meant an atom chosen from O, N and S.
• the invention particularly relates to compounds of general formula (I) above in which X is the group CR 4 R 'and Y is a group NR 6 . Such compounds are represented by the formula (II) below:
• R 1s R 4 , R 4 >, R 6 , R 7 and R 8 are as defined above.
• Such compounds have particularly pronounced and preferential inhibition properties of phosphodiesterase 4.
• a further subject of the invention is also compounds of general formula (I) above in which X is the group NR 4 and Y is the group CR 6 R ⁇ ' .
• Such compounds are represented by the formula (III) below:
• - Z is the oxygen atom and / or
• R 7 and R 8 independently of one another, represent an OR 2 group in which R 2 is a (C ⁇ -C 6 ) alkyl group, preferably an ethyl or methyl group, and / or - R 7 represents a hydrogen atom and R 8 represents a halogen atom or vice versa, and / or
• R 7 and R 8 both represent an ethoxy or methoxy group, and / or
• R 6 and R 6 ' identical or different, represent the hydrogen atom or a (CrC 6 ) alkyl group, and / or
• R 6 represents the hydrogen atom or a (-C ⁇ ) alkyl group and R 6 'is the hydrogen atom, and / or
• X is the group CR 4 R 4 - in which ⁇ and R 'are a hydrogen atom, and / or - Ri is an (C 6 -C 18 ) aryl group, more particularly phenyl, (C 6 -
• C 18 aryl or a (C 5 -C 18 ) heterocycle, aromatic or not, comprising 1 to 3 heteroatoms, optionally substituted.
• a particular family of compounds is represented by the compounds of general formula (II) as defined above in which R 4 and R ′ represent the hydrogen atom.
• a particular family of compounds is represented by the compounds of general formula (II) as defined above in which R 7 and R 8 together form a hydrocarbon chain, such as for example the chain -O-CH 2 -CH 2 -O -.
• Another family comprises the compounds of general formula (I) in which X is the group CR 4 R ', Y is the group NR 6 , Z is the oxygen atom, R 7 and R 8 represent, independently one on the other, an OR 2 group in which R 2 is a (Ci-Ce) alkyl group, R 6 represents the hydrogen atom or a (Ci-Ce) alkyl group and
• R 4 and R 4 ' represent the hydrogen atom.
• Another family includes the compounds of general formula (I) in which X is the group CR 4 R 4 ', Y is the group NR 6 , Z is the oxygen atom, R 7 represents a hydrogen atom and R 8 represents a halogen atom or vice versa.
• Another family includes the compounds of general formula (I) in which X is the group CR 4 R 4 ', Y is the group NR 6 , Z is the oxygen atom, R 7 represents a hydrogen atom and R 8 represents an OR 2 radical in which R 2 is a (C ⁇ -C 6 ) alkyl group.
• the groups R 7 and R 8 independently represent one of the other, a methoxy or ethoxy group, more preferably, they both represent a methoxy or ethoxy group.
• the groups R 6 and R ⁇ ' represent a hydrogen atom or methyl, ethyl or n-propyl group.
• the group R 6 represents a hydrogen atom or a methyl, ethyl or n-propyl group and the group R 6 'is a hydrogen atom.
• the groups R 6 and Rs ′ equal or different, represent a methyl or ethyl group.
• R 4 ′ is the hydrogen atom and, when R 4 is not a hydrogen atom, R 4 more preferably represents a methyl, ethyl, n-propyl, n-dodecyl or benzyl group.
• R 1 advantageously represents an (C 6 -C 18 ) aryl group, (C 6 -C 18 ) aryl (C 1 -C) alkyl, (Ci-C 12 ) alkyl (C 6 ⁇
• C 18 aryl or a heterocycle (C 5 -C 18 ), aromatic or not, comprising 1 to 3 heteroatoms, said group or heterocycle being optionally substituted.
• R 1 is a phenyl group, in particular a substituted phenyl, preferably a phenyl group substituted by:
• halogen atoms in particular chlorine, bromine or iodine, preferably chlorine
• OR 'groups in particular methoxy or ethoxy, or
• an aryl or heterocycle group in particular a phenyl, furyl, pyridyl or thienyl group, said aryl or heterocycle being itself optionally substituted by one or more groups preferably chosen from groups (a) - (e).
• Ri is an aromatic heterocycle, in particular naphthyl, thienyl, furyl, indolyl or pyridyl, optionally substituted by one or more groups preferably chosen from the groups (a) - (f) above .
• Ri is a naphthyl group optionally substituted by one or more groups chosen from the groups (a) - (f) above.
• R 1 is a non-aromatic heterocycle, in particular piperidinyl or isoquinolinyl, optionally substituted by one or more groups preferably chosen from the groups (a) - (f) above.
• groups R 1 which are particularly advantageous for implementing the invention are the 4-chlorophenyl, 3,4-dichlorophenyl, 2-naphthyl, 2 ⁇ benzo [b] thienyl, 4- (2-furyl) groups. phenyl, 3-pyridyl and 3-trifluoromethylphenyl.
• the very particularly preferred compounds are the following:
• the compounds of the invention may be in the form of salts, in particular basic or acid addition salts, preferably compatible with pharmaceutical use.
• pharmaceutically acceptable acids non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane acids. or ethanesulfonic, camphoric, etc.
• pharmaceutically acceptable bases non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
• the invention also relates to a composition
• a composition comprising a compound as defined above and a pharmaceutically acceptable vehicle or excipient.
• the compounds or compositions according to the invention can be administered in different ways and in different forms.
• they can be administered systemically, orally, by inhalation or by injection, such as for example by intravenous, intramuscular, subcutaneous, trans-dermal, intra-arterial, etc., intravenous routes, intramuscular, subcutaneous, oral and inhalation are preferred.
• the compounds are generally packaged in the form of liquid suspensions, which can be injected using syringes or infusions, for example.
• the compounds are generally dissolved in saline, physiological, isotonic, buffered solutions, etc., compatible with pharmaceutical use and known to those skilled in the art.
• compositions can contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc.
• Agents or vehicles which can be used in liquid and / or injectable formulations are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, etc.
• the compounds can also be administered in the form of gels, oils, tablets, suppositories, powders, capsules, capsules, aerosols, etc., optionally by means of dosage forms or devices ensuring sustained and / or delayed release.
• an agent such as cellulose, carbonates or starches is advantageously used.
• the flow rate and / or the dose injected can be adapted by a person skilled in the art depending on the patient, the pathology concerned, the mode of administration, etc.
• the compounds are administered in doses which can vary between 0.1 ⁇ g and 100 mg / kg of body weight, more generally from 0.01 to 10 mg / kg, typically between 0.1 and 10 mg / kg.
• repeated injections may be if applicable.
• delayed or prolonged systems can be advantageous.
• the compounds according to the invention can act on different phosphodiesterases of the cyclic nucleotides, in particular PDE4, and can also have an action on certain subtypes of PDE.
• PDE4A-D four subtypes of PDE4 have been identified, designated PDE4A-D.
• the compounds of the invention may exhibit particular biological effects depending on the PDE4 subtype affected.
• the compounds of the invention can be (selective) inhibitors of PDE-4A, PDE-4B, PDE-4C and / or PDE-4D.
• Compounds of the invention PDE-4B inhibitors are particularly useful for the treatment of the inflammatory component of depression, psychiatric disorders or obesity, for example.
• PDE4 inhibitors are particularly advantageous in the treatment of pathologies relating to inflammation and bronchial relaxation, and more particularly in asthma and chronic obstructive pulmonary disease, but also in other conditions such as rhinitis, syndrome acute respiratory distress, allergies, skin disorders, such as dermatitis, psoriasis, rheumatoid arthritis, autoimmune diseases, multiple sclerosis (including multiple sclerosis), dyskinesia, glomerulonephritis, osteoarthritis, cancer , septic shock, AIDS or obesity.
• the compounds of the invention are also particularly advantageous for the treatment of inflammatory pathologies of the central nervous system, such as more specifically for the treatment of an inflammatory pathology chosen from depression, schizophrenia, bipolar disorder, defect disorders. attention, fibromyalgia, epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and dementia of Lewy bodies (“Le y body dementia”).
• the invention can also be used for the treatment of inflammatory pathologies such as Crohn's disease.
• a particular object of the invention therefore resides in the use of the compounds as described above for the preparation of a medicament intended for the treatment of inflammatory disorders of the nervous system, especially central, of chronic or acute nature.
• a more particular object resides in the use of the compounds as described above for the preparation of a medicament intended for the treatment of inflammatory pathologies of the central nervous system (e.g., neuroinflammation).
• treatment designates both a preventive and a curative treatment, which can be used alone or in combination with other agents or treatments.
• it may be a treatment for chronic or acute disorders.
• the present invention also relates to the use of the compounds described as an anti-inflammatory agent, for example for the treatment of osteoporosis or rheumatoid arthritis.
• the preferred compounds of the invention advantageously have a potent inhibitory activity on one or more PDE4 subtypes.
• the preferred compounds of the invention also exhibit an advantageous selectivity profile, in particular a weak activity with respect to PDE3.
• the compounds of the invention can be prepared from commercial products, using a combination of chemical reactions known to those skilled in the art.
• Figures 1 and 2 show reaction schemes for the synthesis of the compounds of formula (I).
• the compounds of general formula (III) according to the invention in which Z is an oxygen atom can be obtained from a compound of formula (VI)
• R ⁇ R 6 , R 6 >, R 7 and R 8 are as defined above by reaction with an alkyl halide in the presence of potassium carbonate at room temperature.
• the reaction is carried out in a polar aprotic solvent, for example DMF.
• the compounds of general formula (VI) can be prepared by a process comprising the following stages: a) reaction of a compound of general formula (IV)
• the acylating agent of step a) is preferably an acyl halide, in particular an acyl chloride.
• the reaction is advantageously carried out in the presence of a Lewis acid such as SnCl, in an inert solvent at room temperature. Mention may be made, as solvents, of hydrocarbons and their halogen derivatives, for example CHC1 3 .
• the product obtained is taken up in an alcohol, for example methanol and the reaction is continued at room temperature.
• Step b) is advantageously carried out in the presence of hydrazine hydrate, for example in an alcohol, at a temperature of between 100 and 150 ° C. preferably around 150 ° C in a sealed tube for a period of between 3 and 10 hours, preferably about 3 hours, and continued in the presence of an acid, for example acetic acid at reflux of ethanol for a duration of 20 to 60 minutes.
• the compounds of general formula (III) according to the invention can also be obtained directly from a compound of general formula (V) as defined above, by reaction in the presence of a substituted hydrazine, for example methylhydrazine .
• This reaction is advantageously carried out in an alcohol, for example ethanol, at a temperature between 100 and 150 ° C, preferably around 150 ° C, in a sealed tube for a period of between 3 and 10 hours, preferably d 'about 3 hours, and continued in the presence of an acid, for example acetic acid at reflux of ethanol for a period of 20 to 60 minutes.
• the compounds of general formula (III) according to the invention in which Z is an oxygen atom can be prepared from a compound of general formula (XIV)
• R 4 R 6 , R 6 ' 5 R 7 and R 8 are as defined above and G is an activating group such as a halogen (for example Cl or Br) or an O-triflate group, by a Palladium coupling reaction in the presence of boronic acid or ester, alkyn-1-yl or organometallics such as organozincics or organostannans.
• G is a halogen atom
• the compound (III) can also be prepared by a substitution reaction in the presence of a nucleophilic agent, such as an amine for example, in PEtOH.
• the compounds of general formula (XIV) can be obtained by a process comprising:
• R ⁇ R 6 , R 6 ', R 7 , R 8 and G are as defined above;
• R, R 4 >, R 6 , R 7 , R 8 and G are as defined above, by reaction with an acidic compound from the group Ri in the presence of a Palladium catalyst, as shown in the figure 2.
• the reaction is advantageously carried out in a solvent of DMF type at a temperature between 80 and 150 ° C.
• the compounds of general formula (XVIII) can be obtained by a process as shown in FIG. 2 and comprising:
• POCl 3 or POBr 3 preferably at a temperature between 80 and 150 ° C in the middle
• the compounds of formula (II) in which Z is a sulfur atom can be obtained from the compounds of formula (II) in which Z is an oxygen atom by reaction with the Lawesson reagent in toluene at reflux.
• Ri, R 4 >, R 7 , R 8 are as defined above, by reaction with an alkyl halide, preferably in a solvent of DMF or THF type in the presence of a base, of type NaH or K CO 3 , preferably at room temperature (18-25 ° C).
• Example Vaa 1-naphthoyl chloride
• benzoyl chloride the title product is obtained in the same way. YId: 85%.
• Example Vab 3,4-dimethoxyphenyl methyl acetate with ethyl 2- (3,4-diethoxyphenyl) butyrate, the title product is obtained in the same way. Yid: 46%.
• 0.84-1.58 (m, 11H, 3 x CH 3 and CH 2 ), 1.84-2.40 (m, 2H, CHCH 2 ), 3.09-3.16 (m, IH, CH ), 4.03-4.25 (m, 4H, 2 x CH 2 ), 6.77-6.84 (m, IH Ar), 7.14 (s, IH Ar), 7.34-7, 46 (m, 3H Ar), 7.72-7.90 (m, 2H Ar), 8.46-8.54 (m, exchangeable IH, NH).
• IIIba 1- (2-benzo [b] thienyl) -7,8-diethoxy-5-ethyl-3-methyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one Illbb. 1- (2-benzo [b] thienyl) -7,8-diethoxy-3-methyl-5-n-propyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one IIIbc.
• Example IHac By replacing, in Example IHac, benzyl bromide with methyl 12-bromododecanoate, the title product is similarly obtained in the form of a colorless oil. Yield: 99.
• Example IIaa By replacing, in Example Ilaa, benzene boronic acid with (1-tert-butyloxycarbonylindole) -5-boronic acid, the title product is obtained in the same way. Yid: 21%. Mp: 148-151 ° C.
• Example Ilaa By replacing, in Example Ilaa, benzene boronic acid with (1-tert-butyloxycarbonylindole) -2-boronic acid, the title product is obtained in the same way. Yid: 21%. Mp: 146-148 ° C.
• Example XXIaa 3,4-dimethoxyaniline with 3-ethoxy-4-methoxyaniline (XXaa).
• XXaa 3-ethoxy-4-methoxyaniline
• Example XXIaa 3,4-dimethoxyaniline with 4-methoxyaniline. Purify by chromatography (AcOEt 1 / Hexane 3), the title product is obtained in the same way. Yid: 43%.
• 1H-NMR (CDC1 3 , 300MHz): ⁇ 3.66 (s, 3H, OCH 3 ), 5.72 (s, 2H exchangeable, -NH 2 ), 6.73 (d, IH Ar), 6.96 -7.02 (m, 2H Ar), 7.44-7.54 (m, 3H Ar), 7.67-7.70 (m, 2H Ar).
• Example XXIIaa By replacing, in Example XXIIaa, the hydrochloride of ethyl glycinate with the hydrochloride of ethyl phenylalalinate, the title product is obtained in the same way. Yid: 55%. Mp: 216-218 ° C.
• Example XXIIaa the hydrochloride of ethyl glycinate with the dihydrochloride of ethyl histidinate, the title product is obtained in the same way. Yid: 5%. MP: 195 ° C, degradation.
• Example XXIIaa the hydrochloride of ethyl glycinate with the dihydrochloride of ethyl tryptophanate, the title product is obtained in the same way. Yid: 10%. M: 180-185 ° C.
• Example XXIIaa By replacing, in Example XXIIaa, the hydrochloride of ethyl glycinate with the hydrochloride of ethyl L-phenylalalinate, the title product is obtained in the same way. Yid: 50%.
• Mass: (M + H) + 387.14.
• Example XXIIaa the hydrochloride of ethyl glycinate with the hydrochloride of 377 lysine Z, the title product is obtained in the same way. Yid: 20%. Mp: 95-98 ° C.
• a 3 g segment of bovine aorta media fragmented using scissors was homogenized using an ultra-turrax then a glass-glass potter in 7 volumes / weight of buffer A containing a cocktail.
• protease inhibitors (20 mM Tris-HCl, 0.25 M sucrose, 2mM Mg acetate, ImM dithiothreitol, 5mM EGTA, 2000 U / ml aprotinin, 10 mg / 1 leupeptin and 10 mg / 1 trypsin inhibitor soy).
• the homogenate was centrifuged for 1 h at 105,000 g.
• the supernatant was placed on a DEAE-Sephacel column (15 X 1.6 cm), pre-equilibrated with buffer B (buffer A devoid of sucrose, EGTA and protease inhibitors). The column was washed until no absorption could be detected at 280 nm, then eluted with a linear NaCl gradient (0-0.5M) in buffer B. 3 ml fractions were collected and the enzymatic activities were determined under the conditions described below to locate the different PDE1s, PDE3s, PDE4s and PDE5s which were aliquoted and frozen at -80 ° C (Lugnier et al., Biochem. Phamacol., 35 (1986) 1746 -1751). PDE2 was prepared using the same techniques from bovine endothelial cells (Lugnier and Schini, Biochem. Pharmacol. 1990, 39; 75-84).
• the activity of the phosphodiesterase of the cyclic nucleotides was determined using a radioenzymatic method using AMP or tritiated cyclic GMP (1 ⁇ M) as substrate (Lugnier et al., 1986).
• the adenosine or tritiated guanosine monophosphate formed by hydrolysis of the labeled cyclic nucleotide was, in a second incubation with an excess nucleotidase, transformed into adenosine or tritiated guanosine.
• the nucleoside formed was separated from the nucleotides by chromatography on an anion exchange resin.
• the radioactivity of the nucleoside was determined by liquid scintillation.
• the enzymatic incubations were carried out under conditions where there is no more than 15% hydrolysis of the substrate, each point being in fact in duplicate.
• results observed show marked inhibition in a dose-dependent manner of the production of TNF ⁇ and only the latter (relative to ILl ⁇ , IL6 and IL8 which are not significantly reduced) by the compounds tested.
• the compound IHab and Hda at a concentration of 1 ⁇ M inhibits 100% "the production of TNF ⁇ , while at this same concentration, the secretion rates of IL1 ⁇ , IL6 and IL8 are not at all changed.
• Other compounds selected as powerful PDE 4 inhibitors for example Ildh, XXIIag, are also powerful as anti TNF ⁇ , with IC5 0 values between 1 and 0.1 ⁇ m. Some of them, for example XXIIag, are capable of inhibiting the secretion of TNF ⁇ , but also of ILl ⁇ , and have a pharmacological profile distinct from the selective anti TNF ⁇ .

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